It has been estimated that approximately one out of every three Americans will develop cancer at some point during life. Currently, in spite of intensive research and some major advances in treatment, cancer claims the life of nearly one out of every four Americans.
It is indisputable, therefore, that a cure for the various types of cancer is highly needed. Several cancer chemotherapeutic drugs are known, for example, carmustine, doxorubicin, methotrexate, TAXOL.RTM., nitrogen mustard, procarbazine, and vinblastine, to name only a few.
Many of the chemotherapeutic drugs also produce undesirable side effects in the patient. For example, U.S. Pat. No. 4,717,726 reportedly discloses a compound suitable for inhibiting the growth of certain types of malignant neoplasms in mammals. See also Plowman et al., Cancer Res., 12, 1909-1915 (1989). The disclosed compound, 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine, also known as penclomedine, is not satisfactory as a chemotherapeutic, however, because it is known to produce certain undesirable side effects especially in the central nervous system.
Neurological and hematological toxicities of penclomedine have been reported in preclinical and early clinical studies. Dose related neurotoxicity, consisting of muscle tremors, incoordination, convulsions and reduced activity, has been observed in rats. Neurotoxicity appears to be related to peak plasma drug concentrations, as it developed during or immediately after infusion and could be ameliorated by decreasing the rate of drug administration. In dogs, severe emesis and seizures have been associated with plasma penclomedine levels above 30 .mu.M. Neurotoxicity, consisting of dysmetria, ataxia, and vertigo, was also the principal dose limiting toxicity of penclomedine administered as a one hour infusion for 5 consecutive days in patients with advanced solid tumors. The presence of these toxicities, at much lower peak plasma concentrations compared to those reported in preclinical studies, may preclude the administration of higher doses of penclomedine and the achievement of concentrations associated with optimal antitumor activity. Berlin et al., Proc. Amer. Assoc. Cancer Res., 36, 238 (1995); O'Reilly et al., Proc. Amer. Soc. Clin. Oncol., 14, 471 (1995).
Some relevant background art can be found in O'Reilly et al., Clinical Cancer Research, 2, 541-548 (March 1996). This reference describes a study to assess the distribution of .sup.14 C-penclomedine in the tissues and tumors of tumor-bearing rats. The study found that the predominant radioactive species in the brain was .sup.14 C-penclomedine which may explain the observed neurotoxicity of the drug.
Thus, while penclomedine has been tried as an antitumor agent, there remains a need for improved drugs that are effective in combating cancer, but at the same time produce relatively reduced side effects in the patient. An object of the invention, therefore, is to address the above need.